What Is Sulfamethoxazole?

The chemical name of sulfamethoxazole is N- (5-methyl-3-isoxazolyl) -4-aminobenzenesulfonamide. It is a white crystalline powder; it is odorless and slightly bitter. Almost insoluble in water; soluble in dilute hydrochloric acid, sodium hydroxide test solution or ammonia test solution. It is mainly used for urinary tract infections, respiratory infections, intestinal infections, biliary infections and local soft tissue or wound infections caused by sensitive bacteria.

Sulfamethoxazole

The chemical name of sulfamethoxazole is N- (5-methyl-3-isoxazolyl) -4-aminobenzenesulfonamide. It is a white crystalline powder; it is odorless and slightly bitter. Almost insoluble in water; soluble in dilute hydrochloric acid, sodium hydroxide test solution or ammonia test solution. It is mainly used for urinary tract infections, respiratory infections, intestinal infections, biliary infections and local soft tissue or wound infections caused by sensitive bacteria.

On October 27, 2017, the list of carcinogens published by the International Agency for Research on Cancer of the World Health Organization initially compiled the reference, and sulfamethoxazole was in the list of Class 3 carcinogens.

Chinese name

Sulfamethoxazole

Foreign name

Sulfamethoxazole

CAS number

723-46-6

Molecular formula

C10H11N3O3S

Source (name), content (potency)

This product is N- (5-methyl-3-isooxazolyl) -4-aminobenzenesulfonamide. Calculated on dry basis, containing C10H11N3O3S shall not be less than 99.0%.

Character

This product is a white crystalline powder; odorless and slightly bitter.

This product is almost insoluble in water; soluble in dilute hydrochloric acid, sodium hydroxide test solution or ammonia test solution.

Melting point

The melting point of this product (Appendix VIC of Part Two of the 2010 Pharmacopoeia) is 168 ~ 172 ° C.

Identify

(1) Take about 0.1g of this product, add 3ml each of water and 0.4% sodium hydroxide solution, shake to dissolve, filter, take the filtrate, add 1 drop of copper sulfate test solution, and then generate grass green precipitate Azole difference).

(2) The infrared light absorption spectrum of this product should be the same as that of the control ("Infrared Spectra of Drugs" 565).

(3) Identification of the first aromatic amines (Appendix III of Part Two of the 2010 Pharmacopoeia).

an examination

acidity

Take 1.0g of this product, add 10ml of water, shake well, determine according to law (Appendix VI H of the second edition of the Pharmacopoeia, 2010 edition), the pH value should be 4.0 ~ 6.0.

Clarity and color of alkaline solution

Take 1.0g of this product, add 5ml of sodium hydroxide test solution and 20ml of water to dissolve, the solution should be clear and colorless; if it is turbid, compare with No. 1 turbidity standard solution (Appendix B of Part Two of the 2010 Pharmacopoeia) ; If the color is developed, it must not be deeper compared with the control solution (take 12.5ml of yellow No. 3 colorimetric solution and add water to 25ml).

chloride

Take 2.0g of this product, add 100ml of water, shake, and filter; separate 25ml of the filtrate, check according to law (Appendix A of Part II of the 2010 Pharmacopoeia), and compare with a control solution made of 5.0ml of standard sodium chloride solution, it must not be more concentrated (0.01%).

Sulfate

Take 25ml of the remaining filtrate under chloride and check it according to law (Appendix B of Part II of the Pharmacopoeia 2010), compared with the control solution made from 1.0ml of standard potassium sulfate solution, it must not be more concentrated (0.02%).

relative substance

Take this product, add ethanol-concentrated ammonia solution (9: 1) to make a solution containing about 10mg per 1ml, as the test solution; take a precise amount, dilute with ethanol-concentrated ammonia solution (9: 1) to make A solution containing about 50 g per 1 ml was used as a control solution. According to the thin layer chromatography (2010 edition Pharmacopoeia Part II Appendix VB) test, draw 10 l each of the two solutions, and point them on the same silica gel H thin-layer plate with 0.1% sodium carboxymethyl cellulose as the binder. Chloromethane-methanol-dimethylformamide (20: 2: 1) was used as a developing agent, developed, air-dried, and sprayed with ethanol-made p-dimethylaminobenzaldehyde test solution to develop color. If the test solution shows obvious spots of impurities, it must not be deeper than the main spots of the control solution.

Loss on drying

Take this product and dry it at 105 ° C to constant weight, and the weight loss shall not exceed 0.5% (Appendix L of Pharmacopoeia Part II of 2010 Edition).

Residue on ignition

Must not exceed 0.1% (Appendix N of Part Two of the 2010 Pharmacopoeia).

Heavy metal

Take the solution under the clarity and color of the alkaline solution and check it according to law (Appendix H of the 2010 edition of the Pharmacopoeia, the third method). The heavy metal must not exceed 15 parts per million.

Assay

Take about 0.5g of this product, accurately weigh, add 25ml of hydrochloric acid solution (1 2), add 25ml of water, shake to dissolve, and titrate according to the permanent stop titration method (Appendix A of the second edition of the Pharmacopoeia of the 2010 edition), titrate with sodium nitrite Liquid (0.1mol / L) titration. Each 1ml of sodium nitrite titration solution (0.1mol / L) is equivalent to 25.33mg of C10H11N3O3S. ^[2]

Overview

Sulfamethoxazole, also known as neonomine, is a broad-spectrum antibacterial drug. It has a particularly strong effect on staphylococci and E. coli and is used to treat urinary tract infections and avian cholera. Sulfamethoxazole is a middle-effect sulfa drug used systemically. It can compete with PABA on the dihydrofolate synthase in bacteria, prevent the synthesis of bacterial dihydrofolate, and inhibit the growth and reproduction of bacteria. With sulfadiazine, sulfamethoxazole, and trisulfadiazine three sulfa drugs are currently better drugs for the treatment of nocardiosis. The half-life is 10-12 hours and can be partially acetylated. Although this product requires fewer medications than sulfaisoxazole (2 times instead of 4 times a day), its acetylated metabolites have a lower solubility in urine, so the possibility of crystal urine is slightly higher, patients Sufficient hydration should be maintained (adult urine volume is not less than 1,500ml). When used in combination with the synergist trimethoprim, the antibacterial effect is significantly enhanced. Compound neonomine (sulfamethoxazole / trimethoprim (SMZ / TMP)) is often better than monotherapy (see dihydrofolate reductase). Inhibitors [Dihydrofolate Reductase Inhibitors]). It is commonly used in the treatment of urinary tract infections, respiratory tract infections, typhoid fever, and salmonella infections, pneumocystis carinii, nocardiosis, etc., and can also be used to prevent epidemic meningitis. Some clinicians advocate the combination of minocycline, ampicillin, or erythromycin with sulfamethoxazole to treat such infections, but there is no clinical data to prove that the combination treatment is better than sulfamethoxone alone. Compound neonomine (TMP / SMZ), minocy-cline (Minocin) and amikacin (amikacin) can also be used for the treatment of Nocardia spp. Infection.

Pharmacological action

Sulfamethoxazole Sulfamethoxazole belongs to the middle-effect sulfa drugs used systemically and is a broad-spectrum bacteriostatic agent. Its antibacterial action mechanism is because it is structurally similar to p-aminobenzoic acid (PABA), and can compete with PABA on the dihydrofolate synthase in bacteria, preventing the synthesis of bacterial dihydrofolate, thereby inhibiting the growth and reproduction of bacteria. Sulfamethoxazole has antibacterial activity against both Gram-positive and negative bacteria, but the current resistance of bacteria to this class of drugs is common. Staphylococcus, Neisseria, Meningococcus, Enterobacter bacteria Both are increasing. In addition, sulfamethoxazole is also active against microorganisms such as Chlamydia trachomatis, nucleus astragalus, Plasmodium falciparum, and Toxoplasma gondii in vitro.

Pharmacokinetics

Sulfamethoxazole is well absorbed after oral administration (about 90% of the absorbed dose), but it is absorbed slowly. Peak plasma concentrations were reached 2 to 4 hours after administration. After a single oral administration of 2g, the free drug concentration in the blood can reach 80-100 g / ml. The distribution volume of sulfamethoxazole is about 0.15L / kg. After absorption, the drug is widely distributed in systemic tissues and various extracellular fluids such as pleural fluid, peritoneal fluid, synovial fluid, aqueous humor, saliva, sweat, urine, and bile, but it cannot enter the intracellular fluid. Sulfamethoxazole can enter the cerebrospinal fluid through the blood-cerebrospinal fluid barrier, as well as into breast milk and through the placental barrier. When there is no inflammation in the meninges, it can reach 55.6% of the blood concentration in the same period, and in meningitis, it can reach 80% to 90% of the blood concentration. The sulfamethoxazole protein binding rate is 60% to 70%. The protein binding rate can be reduced in patients with severe renal impairment. The elimination half-life of normal renal function is 6 to 12 hours, and that of renal failure can be extended to 20 to 50 hours. The drug is mainly metabolized in the liver to acetylate with no antibacterial activity, and the acetylation rate in blood is 20% to 40%. Patients with liver dysfunction have reduced metabolism, and some drugs combine with glucuronic acid in the liver to form inactive metabolites, which are excreted in the urine. Renal insufficiency drugs are slowly excreted through the kidneys, and acetylation is enhanced. Sulfamethoxazole is mainly excreted by glomerular filtration, and some free drugs can be reabsorbed through the renal tubules. Drug excretion is related to urine pH and increased excretion in alkaline urine. Within 24 hours after the administration, 20% to 40% of the administration amount is excreted in the urine through the urine. In addition, a small amount of drugs are excreted in feces, milk, and bile. Hemodialysis can partially clear the drug, but peritoneal dialysis has no effect.

Indications:

Sulfonamides are broad-spectrum antibacterials, but because many common clinical pathogens are resistant to these drugs, they are only used for infections caused by sensitive bacteria and other sensitive pathogenic microorganisms.

The indications for sulfamethoxazole (excluding the combination of this class of drugs and trimethoprim) are as follows:

1. Acute simple urinary tract infection caused by sensitive bacteria;

2. Combined with trimethoprim to treat otitis media caused by Haemophilus influenzae, Streptococcus pneumoniae and other streptococci that are sensitive to them;

3. Astronomy

4. Adjuvant medication for the treatment of chloroquine-resistant malaria;

5. Toxoplasmosis caused by toxoplasma gondii in combination with pyrimethamine;

6. Secondary drug for treating cervicitis and urethritis caused by Chlamydia trachomatis;

7. Secondary drug for treating soft chancre caused by Haemophilus ducreyi;

8. Secondary drug for treating neonatal inclusion body conjunctivitis caused by Chlamydia trachomatis;

9. Sensitive Neisseria meningitidis can be used as a preventive medicine when epidemic meningococcal meningitis.

Taboo:

1. Those who are allergic to sulfa drugs are contraindicated.

2. Because this product prevents the metabolism of folic acid and aggravates the deficiency of folate in patients with megaloblastic anemia, it is contraindicated in patients with this disease.

3 This product is contraindicated for pregnant and lactating women.

4 This product is contraindicated for infants younger than 2 months.

5. This product is contraindicated in patients with severe liver and kidney damage.

Dosage

1. Adults: (1) general infection, the first dose is 2g, and then 2g per day, divided into two doses. The course of treatment for urinary tract infection is at least 7-10 days. (2) Dose for renal insufficiency: The dosage for patients with renal insufficiency should be adjusted to 1/2 of the usual amount.

2. Children: For general infections in children over 2 months, the first dose is 50-60mg / kg (the total amount does not exceed 2g), and thereafter 50-50mg / kg will be divided into two doses.

Adverse reactions:

1. Allergic reactions are more common and can be manifested as drug eruption. In severe cases, exudative erythema multiforme, exfoliative dermatitis, and bullous epidermolysis atrophic dermatitis can occur. There are also photosensitivity reactions, drug fever, joint and muscle pain, fever And other serum sickness-like reactions.

2. Neutropenia or deficiency, thrombocytopenia, and aplastic anemia. Patients may present with sore throat, fever, paleness and bleeding tendency.

3 Hemolytic anemia and hemoglobinuria. Patients lacking glucose-6-phosphate dehydrogenase are more likely to occur after application of sulfa drugs, and are more common in neonates and children than adults.

4 Hyperbilirubinemia and neonatal jaundice. Because sulfa drugs compete with bilirubin for protein binding sites. Can cause increased free bilirubin. Newborn liver function is imperfect, so it is more prone to hyperbilirubinemia and neonatal jaundice, and nuclear jaundice may occur occasionally.

5. Liver damage. Jaundice and liver failure may occur, and acute liver necrosis may occur in severe cases.

6. Kidney damage. Due to its high solubility in urine (free form and acetylate), crystalline urine and hematuria are rare. Occasionally patients have severe adverse reactions such as interstitial nephritis or tubular necrosis.

7. Nausea, vomiting, decreased appetite, diarrhea, headache, fatigue, etc. The general symptoms are mild and do not affect continued medication. Occasionally, C. difficile enteritis occurs and the drug needs to be discontinued at this time.

8. Goiter and hypofunction occur occasionally.

9. Central nervous system toxicity can occur occasionally, manifested as confusion, disorientation, hallucinations, euphoria or depression. Discontinue medication as soon as it appears.

Although severe adverse reactions caused by sulfa drugs are rare, they can be fatal, such as exudative erythema polymorpha, exfoliative dermatitis, bullous epidermolysis atrophic dermatitis, fulminant liver necrosis, agranulocytosis, aplastic anemia Wait for abnormal blood system. Close observation should be performed during treatment, and the drug should be stopped immediately when early signs of rash or other reactions appear.

Precautions:

1. Cross-allergic reactions. Patients who are allergic to one sulfa drug may also be allergic to other sulfa drugs.

2. Liver damage. Jaundice and liver failure may occur, and acute liver necrosis may occur in severe cases. Therefore, patients with liver damage should avoid systemic application of sulfa drugs.

3. Kidney damage. If this product is used for a long course of treatment, a large dose should be taken with sodium bicarbonate and drink plenty of water to prevent this adverse reaction. Dehydration, shock, and elderly patients are prone to kidney damage when using this product. Use this product with caution or avoidance. This product should not be used in patients with impaired renal function.

4. Patients who are allergic to furosemide, sulfones, thiazines, diuretics, sulfonylureas, and carbonic anhydrase inhibitors can also be allergic to sulfa drugs.

5. The following conditions should be used with caution in patients with G-6PD deficiency and hematoporphyria.

6. It is necessary to pay attention to the examination during treatment. (1) Whole blood examination is particularly important for patients who have received a longer course of treatment.
   (2) Regular urine examination during treatment.
   (3) Liver and kidney function tests.

Medication for pregnant and lactating women:

1. This product can cross the blood placental barrier into the fetus. Animal experiments have found teratogenic effects. Human research lacks sufficient information, and pregnant women should avoid using it.

2. This product can be secreted from milk, the concentration in milk can reach about 50% to 100% of the blood concentration of the mother, the drug may affect the baby. The application of this product in newborns with glucose-6-phosphate dehydrogenase deficiency may lead to the occurrence of hemolytic anemia. In view of the above reasons, this product is not suitable for lactating women.

Medication for children:

Because sulfa drugs can compete with bilirubin for binding sites on plasma proteins, and the acetyltransferase system of newborns is not fully developed, the free blood concentration of sulfa drugs is increased, which increases the risk of nuclear jaundice. Therefore, this class of drugs Application in neonates and infants under 2 months is contraindicated; as children are in the growth and development stage, liver and kidney function is not yet perfect, the dosage should be reduced.

Elderly medication:

Elderly patients have an increased chance of serious adverse reactions with sulfa drugs. Such as severe rash, bone marrow suppression and thrombocytopenia are common in severe adverse reactions in the elderly. Therefore, it should be avoided in elderly patients, and the pros and cons should be weighed when there are indications.

medicine interactions:

1. Combination of urinary alkalizing drugs can increase the solubility of this product in alkaline urine and increase excretion.

2. Can not be combined with para-aminobenzoic acid (PABA), because PABA can be taken up by bacteria instead of this product, the two antagonize each other. It should not be combined with local anesthetics containing parabenzyl, such as procaine, benzocaine, tetracaine, etc.

3 When the following drugs are used together with this product, this product can replace the protein binding site of these drugs, or inhibit their metabolism, so that the drug action time is prolonged or toxicity occurs. Therefore, when these drugs are used simultaneously with this product, or after using this product Need to adjust its dose. Such drugs include oral anticoagulants, oral hypoglycemic agents, methotrexate, phenytoin, and thiopental.

4 When combined with myelosuppressive drugs, they may enhance the adverse reactions of these drugs to the hematopoietic system. If there are indications that the two types of drugs are used together, the possible toxic reactions should be closely observed.

5. Prolonged use with contraceptives (estrogen) can lead to a decrease in the reliability of contraception and an increase in the chance of extramenstrual bleeding.

6. When combined with thrombolytic drugs, their potential toxic effects may be increased.

7. Combination with hepatotoxic drugs may increase the incidence of hepatotoxicity. Liver function should be monitored in such patients, especially those who have been taking the drug for a long time and have a previous history of liver disease.

8. Photosensitivity may occur in combination with light-sensitive drugs.

9. Patients receiving this product have increased requirements for vitamin K.

10 It should not be used in combination with urotropine, because urotropine can be decomposed in acid urine to produce formaldehyde, which can form an insoluble precipitate with this product, which increases the risk of crystallized urine.

11. This product can replace the plasma protein binding site of Baotaisong, which can enhance the effect of Baotaisong when used together.

12. Because this product may interfere with the bactericidal effect of penicillin drugs, it is best to avoid simultaneous application with such drugs.

13. When combined with sulfinpyrazone, it can reduce the secretion of the latter from the renal tubules, leading to an increase in blood concentration and long-lasting, which causes toxicity. Therefore, it may be necessary to adjust this product during or after application dose. When the duration of the sulfazone treatment is long, the blood concentration of the sulfa drug should be monitored to help adjust the dose and ensure safe medication.

Overdose:

The blood concentration of sulfa should not exceed 200 g / ml. If it exceeds this concentration, the incidence of adverse reactions will increase and the toxicity will increase.

Sulfamethoxazole is characterized by slow absorption and excretion, and the effective drug concentration can be maintained for 10-24 hours after one administration. The concentration in the cerebrospinal fluid is 30% to 50% of the blood concentration. It is mainly used for urinary tract infections, respiratory infections, intestinal infections, biliary infections and local soft tissue or wound infections caused by sensitive bacteria. Combination with trimethoprim (TMP) has a good effect on typhoid and paratyphoid.